(S)-methyl 2-(((tert-butoxy)carbonyl)amino)-5-oxonon-8-enoate | 300831-27-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-methyl 2-(((tert-butoxy)carbonyl)amino)-5-oxonon-8-enoate
• 英文别名: (S)-methyl 2-(tert-butoxycarbonylamino)-5-oxonon-8-enoate；methyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxonon-8-enoate
• CAS: 300831-27-0
• 化学式: C₁₅H₂₅NO₅
• 分子量: 299.367
• InChiKey: OGGFNGDWUXJJRC-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  21
• 可旋转键数：
  11
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  81.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-methyl 2-(((tert-butoxy)carbonyl)amino)-5-oxonon-8-enoate 在 詹氏钌催化剂-1 、 水 、 N,N-二异丙基乙胺 、 N,N'-羰基二咪唑 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 sodium hydroxide 、 [双(2-甲氧基乙基)胺]三氟化硫 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 123.0h， 生成 (2R,6S,13aS,14aR,16aS,Z)-6-(((tert-butoxy)carbonyl)amino)-14a-((cyclopropylsulfonyl)carbamoyl)-9,9-difluoro-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydro-1H-cyclopropa(e)pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate
  参考文献：
  名称：

  Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease

  摘要：

  HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a Pl/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.

  DOI：

  10.1021/jm400164c
• 作为产物：
  描述：

  1-O-methyl 7-O-prop-2-enyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxoheptanedioate 在 四(三苯基膦)钯 作用下， 以 DMF (N,N-dimethyl-formamide) 为溶剂， 反应 3.5h， 生成 (S)-methyl 2-(((tert-butoxy)carbonyl)amino)-5-oxonon-8-enoate
  参考文献：
  名称：

  Macrocyclic hepatitis C serine protease inhibitors

  摘要：

  本发明涉及式I、II或III的化合物，或其药用可接受的盐、酯或前药： 其中W是取代或未取代的杂环环系。这些化合物抑制丝氨酸蛋白酶活性，尤其是丙型肝炎病毒（HCV）NS3-NS4A蛋白酶的活性。因此，本发明的化合物干扰丙型肝炎病毒的生命周期，并且还可用作抗病毒剂。本发明进一步涉及包含上述化合物的药物组合物，用于给患有HCV感染的对象进行给药。本发明还涉及通过给主体投药包含本发明化合物的药物组合物来治疗主体HCV感染的方法。

  公开号：

  US20050153877A1

文献信息

• Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors
  申请人：——

  公开号：US20040266668A1

  公开（公告）日：2004-12-30

  The present invention relates to compounds of Formula I or II, or a pharmaceutically acceptable salt, ester, or prodrug, thereof: 1 which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

  本发明涉及式I或II的化合物，或其药学上可接受的盐、酯或前药：1，其抑制丝氨酸蛋白酶活性，特别是乙型肝炎病毒（HCV）NS3-NS4A蛋白酶的活性。因此，本发明的化合物干扰乙型肝炎病毒的生命周期，并且也可用作抗病毒剂。本发明还涉及含有上述化合物的药物组合物，用于治疗患有HCV感染的受试者。该发明还涉及通过给受试者投予含有本发明化合物的药物组合物来治疗HCV感染的方法。
• Synthesis of Conformationally Constrained Dipeptide Mimetics with Azabicyclo[4,3,0]nonanone and Azabicyclo[5,3,0]decanone Scaffolds
  作者：Wanlin Xi、Lei Du、Liping Zhang、Haiying Sun

  DOI：10.1021/acs.joc.0c00399

  日期：2020.8.7

  and efficient method for the synthesis of azabicyclo[4,3,0]nonanone and azabicyclo[5,3,0]decanone amino acid derivatives was developed with the palladium-catalyzed coupling of intermediates 9 and 10 with BocNH2 and Boc2NH and the following reduction of the C–C double bond by hydrogenation as the key steps. The exploration of the synthesis of C6-substituted dipeptide mimetics from 9 and 10 using Suzuki

  利用钯催化的中间体9和10与BocNH 2和Boc 2的偶合偶联反应，开发了一种合成氮杂双环[4,3,0]壬酮和氮杂双环[5,3,0]癸烷氨基酸衍生物的通用有效方法。NH和随后通过氢化还原C–C双键是关键步骤。还进行了使用Suzuki偶联作为关键反应从9和10合成C 6取代的二肽模拟物的探索。
• Synthesis of cis-2,5-disubstituted pyrrolidines via diastereoselective reduction of N-acyl iminium ions
  作者：Alexander C Rudolph、Rainer Machauer、Stephen F Martin

  DOI：10.1016/j.tetlet.2004.04.122

  日期：2004.6

  A new procedure for forming cis-2,5-disubstituted pyrrolidines having unsaturated side chains has been developed that features the diastereoselective reduction of N-acyl iminium ions, which were formed in situ by acid-catalyzed cyclizations of unsaturated γ-keto carbamates, with triphenylsilane. The sequence was applied to a very concise synthesis of 16, a subunit in the nonpeptide cholecystokinin

  已经开发出形成具有不饱和侧链的顺式-2,5-二取代的吡咯烷的新方法，其特征在于通过酸催化不饱和γ-酮氨基甲酸酯的环化反应原位形成的N-酰基亚氨基离子的非对映选择性还原。三苯基硅烷。将该序列应用于非常简洁的16合成，该合成是非肽胆囊收缩素拮抗剂（+）-RP-66803中的一个亚基。
• [EN] MACROCYCLIC PEPTIDES ACTIVE AGAINST THE HEPATITIS C VIRUS<br/>[FR] PEPTIDES MACROCYCLIQUES ACTIFS CONTRE LE VIRUS DE L'HEPATITE C
  申请人：BOEHRINGER INGELHEIM CA LTD

  公开号：WO2000059929A1

  公开（公告）日：2000-10-12

  The present invention covers macrocyclic compounds of formula (I) active in-vitro and in cellular assays against the NS3 protease of the hepatitis C virus wherein W is CH or N; R21 is H, halo, C¿1-6? alkyl, cycloalkyl, haloalkyl, C1-6 alkoxy, cycloalkoxy, hydroxy, or N(R?23)¿2, wherein each R23 is independently H, C¿1-6? alkyl or cycloalkoxy; and R?22¿ is H, halo, C¿1-6? alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C3-6 cycloalkyl, C6 or 10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur; said cycloalkyl, aryl or Het being substituted with R?24¿, wherein R24 is H, C¿1-6? alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R?25)¿2, NH-C(O)-R25; or NH-C(O)-NH-R25, wherein each R25 is independently: H, C¿1-6? alkyl or C3-6 cycloalkyl; or R?24¿ is NH-C(O)-OR26 wherein R26 is C¿1-6? alkyl or C3-6 cycloalkyl; R?3¿ is hydroxy, NH¿2?, or a group of formula -NH-R?31¿, wherein R31 is C6 or 10 aryl, heteroaryl, -C(O)-R32, -C(O)-OR32 or -C(O)-NHR32, wherein R32 is: C¿1-6? alkyl or C3-6 cycloalkyl; D is a 5 to 10-atom saturated or unsaturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S, or N-R?41¿, wherein R41 is H, C¿1-6? alkyl, cycloalkyl or -C(O)-R?42¿, wherein R42 is C¿1-6? alkyl, cycloalkyl or C6 or 10 aryl; R?4¿ is H or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of: C¿1-6? alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio or C1-6 thioalkyl, and A is an amide of formula -C(O)-NH-R?5¿, wherein R5 is selected from the group consisting of: C¿1-8? alkyl, C3-6 cycloalkyl, C6 or 10 aryl or C7-16 aralkyl; or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.

  本发明涵盖了式（I）的大环化合物，该化合物在体外和细胞试验中对丙型肝炎病毒的NS3蛋白酶具有活性，其中W为CH或N; R21为H，卤素，C1-6烷基，环烷基，卤代烷基，C1-6烷氧基，环烷氧基，羟基或N（R23）2，其中每个R23独立地为H，C1-6烷基或环烷氧基; R22为H，卤素，C1-6烷基，C3-6环烷基，C1-6卤代烷基，C1-6硫代烷基，C1-6烷氧基，C3-6环烷氧基，C2-7烷氧基烷基，C3-6环烷基，C6或10芳基或Het，其中Het是含有1至4个从氮，氧和硫选择的杂原子的五元，六元或七元饱和或不饱和杂环; 所述的环烷基，芳基或Het被R24取代，其中R24为H，C1-6烷基，C3-6环烷基，C1-6烷氧基，C3-6环烷氧基，NO2，N（R25）2，NH-C（O）-R25; 或NH-C（O）-NH-R25，其中每个R25独立地为：H，C1-6烷基或C3-6环烷基; 或R24为NH-C（O）-OR26，其中R26为C1-6烷基或C3-6环烷基; R3为羟基，NH2或式-NH-R31的基团，其中R31为C6或10芳基，杂芳基，-C（O）-R32，-C（O）-OR32或-C（O）-NHR32，其中R32为：C1-6烷基或C3-6环烷基; D为5至10个原子的饱和或不饱和烷基链，可选地包含从O，S或N-R41中独立选择的1至3个杂原子，其中R41为H，C1-6烷基，环烷基或-C（O）-R42，其中R42为C1-6烷基，环烷基或C6或10芳基; R4为H或在链D的任何碳原子上的1至3个取代基，所述取代基独立地选择自以下群：C1-6烷基，C1-6卤代烷基，C1-6烷氧基，羟基，卤素，氨基，氧代，硫代或C1-6硫代烷基; A为式-C（O）-NH-R5的酰胺，其中R5选择自以下群：C1-8烷基，C3-6环烷基，C6或10芳基或C7-16芳基烷基; 或A为羧酸或其药学上可接受的盐或酯。
• Macrocyclic peptides active against the hepatitis C virus
  申请人：Boehringer Ingelheim (Canada) Ltd.

  公开号：US20040002448A1

  公开（公告）日：2004-01-01

  The present invention covers macrocyclic compounds of formula I active in-vitro and in cellular assays against the NS3 protease of the hepatitis C virus. 1 wherein W, R 21 , R 22 , R 3 , R 4 , D and A are as defined herein, or a pharmaceutically acceptable salt or ester thereof.

  本发明涵盖了公式I的大环化合物，该化合物在体外和细胞测定中对丙型肝炎病毒的NS3蛋白酶具有活性。 其中，W，R21，R22，R3，R4，D和A如此处所定义，或其药学上可接受的盐或酯。